Hypoparathyroidism is an uncommon human skeletal disorder in which parathyroid hormone (PTH) is markedly decreased or absent from the circulation. It is due primarily to surgical removal of all parathyroid tissue or autoimmune destruction of the parathyroid glands. The absence of PTH leads to a reduction in the serum calcium concentration that can be asymptomatic or associated with symptoms of hypocalcemia. PTH deficiency also leads to major abnormalities in biochemical, densitometric, histomorphometric, biomechanical and cellular properties of the skeleton. Over the past 5 years of funding, we have gained insights into these aspects of the skeleton that are regulated by PTH. This proposal seeks to continue and to expand this investigation in order to gain more complete understanding of PTH's skeletal actions. To this end, in addition to completing our studies of hypoparathyroidism, we will apply our experimental approach to another human skeletal disorder, primary hyperparathyroidism (PHPT), a disorder of excessive PTH. We will use a cotemporaneous experimental design to investigate these two completely different parathyroid disorders, which represent opposite ends of the PTH insufficiency/excess spectrum. The model achieves greater significance because we will correct both PTH disorders, either by replacement of PTH (hypoparathyroidism) or by removal of excess PTH by parathyroid surgery (PHPT). By studying skeletal features before and after correction of states of PTH deficiency or excess, we can assign specific skeletal properties to this molecule. State-of-the-art approaches include methods to assess quantitative structural and dynamic features of the skeleton: dual energy X-ray absorptiometry, quantitative peripheral and central computed tomography (including high resolution pQCT, finite element analysis, Individual Trabecular Segmentation analysis, voxel- based QCT) and measurement of skeletal indices from analysis of iliac crest bone biopsies (histomorphometry, 5CT, synchrotron-based 5CT, quantitative back scattered electron imaging, and Fourier Transform Infrared Spectroscopy). In addition, bone turnover markers and circulating osteoblast precursor cells will be measured. The new knowledge from this proposal will have far wider implications than those associated with an uncommon disease. Rather, we anticipate our results will have far broader implications, including greater understanding both of the normal control of the skeleton by PTH and of the anabolic activity of PTH in the treatment of postmenopausal osteoporosis.